Pneumocystis carinii (PC) pneumonia continues to be a significant problem among immunosuppressed individuals. Moreover, neonatal animals have been shown to harbor subclinical PC infections and more recently it has been shown that a significant proportion of human infants also are either infected or colonized with PC. Very little is known about lung immune responses to PC or other fungal pathogens in neonates. We observed that neonatal mice challenged with an intranasal inoculation of PC fail to mount an inflammatory response before about 3 weeks of age, whereas adult mice mount a response in a matter of a few days. Our goal in the previous funding period was to determine whether this delay in response was due to immaturity of neonatal lymphocytes or whether the neonatal lung environment is suppressive. We established that neonatal lymphocytes are functional when transferred into an adult lung environment and could stimulate clearance of PC infection. However, transfer of adult cells to neonates did not alter the kinetics of inflammation nor clearance of the organisms suggesting that the neonatal lung environment could not support an immune response to PC. There was a significant deficit in the production of proinflammatory cytokines and chemokines in PC-infected neonatal lungs; whereas, TGFI3 and IL-10 mRNA were constitutively expressed in neonatal lungs at levels similar to PC-infected adult lungs. These data suggested that the growth factors involved in postnatal lung development may also be immunosuppressive. For this proposal we have chosen to focus on this immunosuppressive lung environment with the goal of determining whether there is active suppression of inflammation in postnatally developing lungs. We hypothesize that the neonatal lung environment, impacted on by growth factors and innate immune cells, is immunosuppressive toward inflammatory responses against PC. This results in suppressed proinflammatory cytokine and chemokine production and delayed clearance of organisms. The following aims are designed to address this hypothesis: 1) to determine whether lung developmental growth factors are expressed at the protein level in response to PC in infant mice; 2) to determine whether immaturity of innate immune cells and mediators in the lungs suppress immune responses to PC; and 3) to determine whether interruption of negative regulators of immune function in neonatal lungs will promote inflammatory responses to PC. Very little is known regarding the development of immunity in the lungs and understanding this process is vital for protecting young children from potentially life-threatening infections.